Cholesterol Metabolism in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets

Dai, Lingyun; Zou, Li; Meng, Lanxia; Qiang, Guifen; Yan, Mingmin; Zhang, Zhentao

doi:10.1007/s12035-020-02232-6

Cited by 130 publications

(97 citation statements)

References 193 publications

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“…First, approximately a quarter of the body's cholesterol is concentrated in the brain, and lipid composition, including lecithin, omega-3, and cholesterol, account for nearly half of the brain's weight. Although peripheral cholesterol cannot enter the central nervous system because of the blood-brain barrier, it reflects the supplement of cholesterol (Dai et al, 2021). Crucially, cholesterol is an important component of nerve cell membranes and also participates in the metabolic activities of nerve cells.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Increase in Cholesterol Is Associated With Better Cognitive Function: Evidence From a Longitudinal Study

Liu

Zou

Zhou

et al. 2021

Front. Aging Neurosci.

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Background: Higher visit-to-visit cholesterol has been associated with cognitive decline. However, the association between long-term increase or decrease in cholesterol and cognitive decline remains unclear.Methods: A total of 4,915 participants aged ≥45 years with normal cognition in baseline were included. The participants were divided into four groups, namely low–low, low–high, high–low, and high–high, according to the diagnostic thresholds of total cholesterol (TC), non-high-density lipoprotein cholesterol (NHDL-C), low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol (HDL-C) after 4 years of follow-up. Cognitive function was assessed by episodic memory and mental intactness. Binary logistic regression was used to analyse the association of cholesterol variation with cognitive decline.Results: Among the participants, 979 (19.9%) experienced global cognitive decline. The odds ratio (OR) of global cognitive and memory function decline were remarkably lower in participants in the low–high NHDL-C group than those in the low–low group [OR and 95% confidence interval (CI): 0.50 [0.26–0.95] for global cognitive decline, 0.45 [0.25–0.82] for memory function decline]. The lower OR was also significant in females (OR [95% CI]: 0.38 [0.17–0.87] for global cognitive decline; 0.44 [0.19–0.97] for memory function decline) and participants without cardiovascular disease (OR [95% CI]: 0.31 [0.11–0.87] for global cognitive decline; 0.34 [0.14–0.83] for memory function decline). The increases in other cholesterol were also negatively associated with the risk of cognitive decline although not significantly.Conclusions: A longitudinal increase in NHDL-C may be protective for cognition in females or individuals without cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Long-Term Increase in Cholesterol Is Associated With Better Cognitive Function: Evidence From a Longitudinal Study

Liu

Zou

Zhou

et al. 2021

Front. Aging Neurosci.

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“…HMG-CoA reductase (HMGCR) and squalene monooxygenase (SM), both SREBP2 targets, are rate limiting enzymes in this process. Cholesterol is transported from the ER to the plasma membrane without passing through the Golgi ( Dai et al, 2021 ). As an alternative to synthesis, cells can acquire cholesterol trough uptake.…”

Section: Intracellular Cholesterol Metabolism; the Basicsmentioning

confidence: 99%

Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects

Feringa

Kant

2021

Front. Aging Neurosci.

152

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While the central nervous system compromises 2% of our body weight, it harbors up to 25% of the body’s cholesterol. Cholesterol levels in the brain are tightly regulated for physiological brain function, but mounting evidence indicates that excessive cholesterol accumulates in Alzheimer’s disease (AD), where it may drive AD-associated pathological changes. This seems especially relevant for late-onset AD, as several of the major genetic risk factors are functionally associated with cholesterol metabolism. In this review we discuss the different systems that maintain brain cholesterol metabolism in the healthy brain, and how dysregulation of these processes can lead, or contribute to, Alzheimer’s disease. We will also discuss how AD-risk genes might impact cholesterol metabolism and downstream AD pathology. Finally, we will address the major outstanding questions in the field and how recent technical advances in CRISPR/Cas9-gene editing and induced pluripotent stem cell (iPSC)-technology can aid to study these problems.

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“…However, there have been controversies whether increased or decreased levels of blood cholesterol are associated with neurodegeneration. For example, higher, similar, or lower plasma cholesterol have all been reported in the AD and Parkinson's disease cohorts relative to their corresponding controls [126]. These seemingly contradictory results are partly attributed to the differences in disease progression.…”

Section: Impaired Cholesterol Metabolism In Pds and Other Neurodegenerative Diseasesmentioning

confidence: 94%

Peroxisomes in intracellular cholesterol transport: from basic physiology to brain pathology

Xiao

Song

Luo

2021

Explor Neuroprot Ther

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Peroxisomes are actively involved in the metabolism of various lipids including fatty acids, ether phospholipids, bile acids as well as the processing of reactive oxygen and nitrogen species. Recent studies show that peroxisomes can regulate cholesterol homeostasis by mediating cholesterol transport from the lysosomes to the endoplasmic reticulum and towards primary cilium as well. Disruptions of peroxisome biogenesis or functions lead to peroxisomal disorders that usually involve neurological deficits. Peroxisomal dysfunction is also linked to several neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In many peroxisomal disorders and neurodegenerative diseases, aberrant cholesterol accumulation is frequently encountered yet largely neglected. This review discusses the current understanding of the mechanisms by which peroxisomes facilitate cholesterol trafficking within the cell and the pathological conditions related to impaired cholesterol transport by peroxisomes, with the hope to inspire future development of the treatments for peroxisomal disorders and neurodegenerative diseases.

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Cholesterol Metabolism in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets

Cited by 130 publications

References 193 publications

Long-Term Increase in Cholesterol Is Associated With Better Cognitive Function: Evidence From a Longitudinal Study

Long-Term Increase in Cholesterol Is Associated With Better Cognitive Function: Evidence From a Longitudinal Study

Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects

Peroxisomes in intracellular cholesterol transport: from basic physiology to brain pathology

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